A study led by Enrico Lugli reveals an unexpected potential for a readily available compound: sodium chloride, commonly known as “table salt”. When administered to T cells in-vitro before infusion, it boosts their anti-tumor activity in preclinical models of cancer

We regularly use it to flavor the dishes we eat: it’s scientific name is sodium chloride (NaCl). According to new research published in the journal Nature Immunology, the addition of a specific amount of salt could have an unexpected use in preparing cellular therapies against cancer, such as CAR-T or TCR therapies. For these treatments, a patient’s lymphocytes are collected, modified to better recognize cancer cells, and then reinfused into the patient. In laboratory experiments, when salt is administered to T lymphocytes in culture before infusion, it activates the cells and enhance their therapeutic action.

The discovery comes from a group of researchers at IRCCS Humanitas Research Hospital, led by Enrico Lugli, head of the Laboratory of Translational Immunology and of the Flow Cytometry Core. The study was made possible by funding from AIRC Foundation for Cancer Research, and from the prestigious Cancer Research Institute (CRI) of New York, which has supported Enrico Lugli’s laboratory since 2021, when the researcher won the CRI Lloyd J. Old STAR Award.

The research has high translational potential: if future clinical studies confirm the results, salt could become an important, accessible, and cost-effective addition to the combination of cytokines and metabolites already in use in the preparation of cellular therapies against cancer.

The Importance of Awakening the Immune System Against Cancer

In the tumor microenvironment, even the cells that should be most aggressive against cancer, such as CD8 T cells of the immune system, can be inactivated by the tumor, pushing them into a dysfunctional state called “exhaustion,” where the cells are no longer able to perform their function and stop proliferating.

“Understanding and reversing this state of exhaustion is crucial if we want to achieve effective cancer treatments: even frontier therapies like CAR-T, which are based on engineering the immune system to better recognize cancer cells, are at the risk of acquiring the same exhaustion mechanisms,” says Enrico Lugli.

For nearly ten years, the group of researchers led by Lugli has been studying the mechanisms of T cell exhaustion and developing strategies to counteract them, but it was surprising nonetheless to discover the effectiveness of such a common molecule as sodium chloride (NaCl).

“There were already data on the influence of various micronutrients – such as glucose, potassium, magnesium and fats – on immune cells’ function and metabolism, and how micronutrients can push these cells towards pro-inflammatory states. But we knew very little about the role of salt, especially on CD8 T cells,” Lugli continues.

The Discovery and Its Implications in the Fight Against Cancer

The research team discovered that a single addition of NaCl to cells cultured in the lab is capable of awakening them, increasing their persistence and anti-tumor action. The experiments focused on using NaCl in the preparation phase of T cells before infusion: the researchers demonstrated that this preparatory treatment can prevent cell exhaustion once transplanted, likely through the action of one of the two ions that make up salt: sodium (Na).

Further studies conducted in collaboration with Dr. Matteo Simonelli, head of early clinical development of new drugs for Solid Tumors (Phase I Studies) and Neuro-Oncology at the Humanitas Cancer Center, and oncologist and researcher Agnese Losurdo, revealed in fact that higher sodium level in the blood is associated with a better response to cancer immunotherapy, including that with so-called checkpoint inhibitors.

These data, so far primarily obtained in laboratory disease models, undoubtedly need to be validated in a clinical context. Although preliminary, the results suggest that the anti-tumor action of lymphocytes can be enhanced by promoting their NaCl metabolism: “Our results demonstrate that in controlled laboratory environments, sodium chloride significantly impacts the functionality of CD8 T lymphocytes, which are crucial cells in the anti-tumor response. The discovery helps clarifying the role of metabolism in reprogramming the immune system and points to an innovative and sustainable strategy for enhancing cell immunotherapies,” says Enrico Lugli.

It is important to emphasize that the effectiveness of salt in the T cell preparation protocol has nothing to do with dietary salt intake: a prolonged salt-rich diet would not only fail to activate the immune system against cancer – the systemic concentration is still too low – but would also cause severe cardiovascular damage.